B lymphocytes recognize and destroy viruses and bacteria though antibodies. These molecules are secreted during the immune response, when B cells encounter and recognize foreign material on the surface of pathogens. Unlike other genes, antibody genes are assembled by the joining of various DNA segments thorough a reaction known as V(D)J recombination. The enzymes responsible for V(D)J recombination are called RAG1 and RAG2. Recombination occurs very early on in development, when B cells are still maturing in the bone marrow. Once the antibody molecule is placed on the cell surface B cells migrate out of the bone marrow via blood vessels to the periphery, where they scan the environment for foreign materials. Whenever the antibody molecule on the B cell surface is crosslinked by bacterial or viral proteins, B cells become activated and engage in the immune response. One of the most striking aspects of this response is that the affinity of the antibody molecule for foreign proteins increases over time. This is achieved by the introduction of random mutations in the antibody genes by an enzyme called AID. While RAG and AID preferentially target antibody genes, other genomic sites, including the Myc and Pim1 oncogenes, undergo low levels of DNA damage. This off-targeting activity can produce rearrangements that have the potential to deregulate oncogenes, leading to B cell tumor development. Why RAGs and AID are thus promiscuous has been a mystery. This fiscal year our laboratory published three manuscripts that shed some light on this problem. 1- Qian et al, Cell, December 2014. In this manuscript we showed that non-antibody genes promiscuously targeted by AID are predominantly regulated by highly active DNA sequences called super-enhancers. These sequences drive high levels of gene expression and render the DNA accessible to AID recruitment. 2- Meng et al, Cell, December 2014. In collaboration with Frederick W. Alt, from Harvard University, we showed that in addition to super-enhancers, the genes attacked by AID are transcribed (expressed) by polymerases working in both directions (convergent transcription). This activity also appears to render the DNA particularly prone to AID-mediated damage. 3- Teng et al, Cell, August 2015. In collaboration with David Schatz, from Yale University, we showed that RAGs are highly promiscuous in that they are recruited to all sites where there is gene transcription. At the same time, only the sites that carry DNA sequences (RSSs) very similar to those found at antibody genes are actually damaged by RAGs. So bone marrow B cells have developed a safeguard mechanism to avoid too much promiscuous DNA damage by RAG proteins and thus tumor development.